鈣通道阻斷劑的應用進展

CCB & CHD-HT-AR Uptodate 2007,UpToDate (15.1) of Calcium channel blocker (CCB) December 2006 June 2007,高血壓冠心病-心臟性猝死的防治與鈣通道阻斷劑的應用進展,西安交通大學第一附屬醫(yī)院 心內科崔長琮2007年4月15日 寶雞扶風,重視心臟猝死的殘酷現(xiàn)狀,他們的猝然離世為人們敲響了警鐘：小心心臟性猝死！,2003年6月27日，在聯(lián)合會杯的比賽中，喀麥隆國腳 維維安福猝死賽場,54歲的愛立信（中國）有限公司總裁楊邁于 2004年4月8日晚，由于心臟病突發(fā)在京猝死,全球快餐業(yè)巨頭麥當勞 公司董事長兼首席執(zhí)行 官吉姆坎塔盧波在2004 年4月19日凌晨猝死于家中,在雅典采訪的北京電視臺資深攝像記者鄭立，在拍攝奧運火炬?zhèn)鬟f時心臟病突發(fā)猝死，年僅47歲,2005年2月25日，成都社保局 局長向志雄在開會時猝死,2004年10月北京交大 學生劉紅斌和老年運動員胡守禮在參加北京馬拉松比賽中發(fā)生猝死,SCD-ACS & JWS Shanghai 2005-1022, 重點預防和教育 因為心臟猝死只有一個 預防方法： A,B.C,D,E, + ICD. Amiodaron ?,急救 DC / 扣擊處理 CPR 藥物起搏,ACS-JWS-SCD 2006-8-20 Beijing IHF 2006,Early hyperacute phase of A C S and S C D-心臟原因、驟然不可預測、1小時內的自然死亡 (占SCD的),Huikuri HV. N Engl J Med. 2001;345:1473-1482.,40% SCA發(fā)生在睡眠時或沒有旁人在現(xiàn) 場的情況下 1 80% SCA發(fā)生在家里 1 院外SCA的存活率僅 5% 2,3 （美國）,SCA 存活率統(tǒng)計,即使在緊急救護系統(tǒng)非常完善/可早期給予除顫治療的地區(qū)，SCA的存活率仍很低，因為大多數(shù)SCA發(fā)生時無旁人在場，或即便被發(fā)現(xiàn)，也很難在6-8分鐘內給予有效的治療.,1 Swagemakers V. J Am Cardiol. 1997;30:1500-1505.2 Ginsburg W. Am J Emer Med. 1998;16:315-319.3 Cobb LA. Circulation. 1992;85:I98-102.,Lipid lowering with statins UpToDate 13.3 Sep 1, 2005,調脂粑目標的目的是 AS-CHD-SCD,內皮功能和斑塊的動態(tài)平衡,屏障功能：血管內與內皮下組織 之間的屏障作用；分泌功能：分泌 NO ET ，促凝抗凝等；調節(jié)功能：調節(jié)血管的收收縮和舒張，調節(jié)血壓；,Pathogenesis of atherosclerosis Charles E Rackley, UpToDate (14.1) February 2006. HISTOLOGY 1-Fatty streaks 2-Fibrous plaque 3-Advanced lesions PATHOGENESIS 1-Endothelial dysfunction 2-Dyslipidemia 3-Inflammation 4-Serum CRP - 5-Cytokines 6-Leukocyte activation 7-Toll-like receptor 4 8-Plaque hemorrhage 9-Plaque rupture 10-Tissue factor 11-Angiotensin II 12-Endothelin-1 13-Adhesion molecules 14-Flow characteristics 15-Anti-oxidized LDL antibodies 16- Infection 17-C. pneumoniae infection 18 H. pylori - 19-Cytomegalovirus infection 20-Pathogen burden - 21-Effect of antimicrobial therapy - 22-Effect of vaccination,影響內皮功能動脈平衡的各種因素 （自Charles E Rackley, UpToDate (14.1), February 2006.）促進內皮功能障礙的因素 保護和修復內皮功能的因素和干預措施 增齡性因素，年齡40歲 心態(tài)平衡 性別因素，男性女性 雌性素 冠心病的家族史 MEF2A AA1 抽煙 戒煙 血膽固醇或LDL膽固醇增加 降膽固醇或LDL的藥物 血HDL膽固醇減少 他汀類藥物的應用 高血壓 降壓藥物，ACEI/ARB的應用 高血糖或糖尿病 降糖治療 肥胖 控制體重 少運動 運動 高脂飲食 合理飲食 血清半胱氨酸增加,高半胱氨酸血癥,內 皮 功 能 障 礙,慢 性 炎 癥,高尿酸血癥,高血壓,遺傳因素MEF2A,吸煙,低HDLTC/HLD/H,高LDLTGTC,糖尿病,促凝與抗凝紊亂,交感副交感紊亂,其他感染,螺旋桿菌,衣原體感染,各種病毒感染,C少動,L肥胖,年齡,家族史,性別,Gibbons et al. J Am Coll Cardiol. 1999;33:2092-2197,AS-CHD-ACS-HT- Stroke-CHF-SCD,SymN+RAS+,一二級預防ABCDE,-,+,T高脂飲食,心態(tài)不平精神緊張,心臟性猝死發(fā)生機制的TDR、心電圖和臨床,Ito-JWS-VT/VFphase 2 reentry,Ikr/Iks TDRQTdVT/VFEAD/DAD reentry,西安交通大學醫(yī)學院第一附屬 醫(yī)院心內科科 的研究表明：,1 -崔長琮 臨床心電學雜志 2007; (1):1 2 - Wang DQ,Cui CZ,Yan GX. J Wave Syndrome. WWW.SCD- 2006,OCT3- Gan-Xin Yan,et al: The First Hospital of Xian Jiaotong Univer sity, - Xian, China. Lankenau Institute for Medical Research, Wynnewood, PA Circulation. 2004;110:1036-1041. 4- Juan Shu, Tiangang Zhu,Lin Yang,Chang-cong Cui, Ganxin Yan,. ST segments elevated in the early repolarization syndrome.Idiopathyic ventricular fibrillarization, and the Brugada syndrome:Cellular and Clinical Linkage Janoury of electrocardiology 2005; 16:1436-95-嚴干新 王東琦 崔長琮。J波與J波綜合征.中華心律失常學雜志 2004;8:360-365,1- Ajay Joshi,Changcong Cui, Gan-Xin Yan Preclinical Strategies to Assess QT Liability and Torsadogenic Potential ofNew Drugs: The Role of Experimental Models. Journal of Electro- cardiology. 2004，37 :7-14 2 Zhongxiang Yu,Changzong Cui,Gan Xin Yan, EnhancedTransmural Dispersion of Repolariza- tion is Essential to the Genesis of the Triggering Beat Capable of Indu cing Torsade de Pointes。Heart Rhythm 2004; 1(1):S124 3-廉姜芳,崔長琮,薛小臨,等. 3個先天性長QT綜合征家族的 基因分型.中華醫(yī)學遺傳學雜志，2004,21(3): 272-273 4-Jiangfang Lian, Changcong Cui, Xiaolin Xue The clinical characteristics and phenotype-genotype correlation in 6 Chinese LQTS families. J of HuaZhong University of Tecnology Science Medical Science, 2004, 24(3): 208-21,ACS-JWS-SCD 2006-8-20 Beijing IHF 2006,J wave Syndrome,1-崔長琮, 陳新. 積極開展心血管離子通道病的基礎和臨床研究. 中華心律失常學雜志。2004; 8（6）:325-327 2-嚴干新 姚青海 王東琦 崔長琮。 J波與J波綜合征。 中華心律失常學雜志。 2004； 8（6）:360-3653-王東琦 崔長琮 嚴干新.心電圖心室復極波的細胞離子流機制與臨床.中華心律失常學雜志 2005；9(6):478-4824-Wang DQ,Cui CZ,Yan GX. J Wave Syndrome. WWW.SCD- 2006,OCT,心電圖在心臟性猝死防治中的應用 2007-3-22,蔡-男，54歲，2004-7-1-17：30C/O; chest uncomfortable for 30min.Fu: 32 moths is well .,超級期AMI的心電圖特點 1- J 點抬高-J波形成 （o.1mV;20ms， 與ST段起始部抬高融合）;2- J 波，與抬高的ST段和T波的上升支融合；3- 但是抬高的融合為一體的J波-ST段和T波的 上升支形成弓背向下的拋物曲線（Sloop done）;4- T波高尖，QT間期正常（0.44ms）或 縮短（0.36ms ）。,LVH-OMI-HFDHM-HFHCM-HF （肥厚型心肌病） HCM是年輕人最常見的死因 SCD發(fā)生危險與左室肥厚存在直接相關性，無臨床癥狀或癥狀輕微但左室肥厚嚴重的年輕患者長期存在SCD的危險。1,2,1 Spirito P. N Engl J Med. 1997;336:775-785. 2 Maron BJ. N Engl J Med. 2000;342:365-373.,CCB & CHD-HT-AR Uptodate 2007,Mechanism of CCB,CCB & CHD-HT-AR Uptodate 2007,CCB,心臟,血管平滑肌,CCB & CHD-HT-AR Uptodate 2007,CCB & CHD-HT-AR Uptodate 2007,CCB與鈣通道 電壓依賴性 鈣通道鈉鈣交換鈣內流和外流,外周動脈血管平滑肌擴展 血壓下降,冠狀動脈血管平滑肌擴展 心絞疼緩解,動脈平滑肌增生減少內皮功能改善 抗動脈硬化,抑制心臟自律性抑制心臟傳導性 抗心律失常,CCB & CHD-HT-AR Uptodate 2007,常用鈣拮抗劑 Calcium Antagonists or CCB 二氫吡啶類鈣拮抗劑- Dihydropyridines, 強效擴血管但不影響心肌收縮力和轉導 硝苯地平 Nifedipine，控釋-拜心同Bayer/30mg qd . 5.6y 緩釋-/30mg qd 短效-心痛定 10mg tid, 不用 拉西地平 Lacidipine，樂息平-GSK 4mg 5.6y/三精司樂平 4mg qd .1.3y 氨氯地平 Amlodipine，絡活喜Pfizer 5mg qd /伏絡清東北.6.6y 非絡地平 Felodipine，波依定AstraZ 5mg qd/. 5.3y Barmidipine 10mg qd Benidipine 4-8mg qd Nicardipine 40mg qd Lercanidipine 10mg qd Isradipine Nisoldipine 非二氫吡啶類鈣拮抗劑- Non-dihydropyridines ,擴血管+ 影響心肌收縮力和轉導 地爾硫卓 Diltiazem, 合心爽 90-120mg qd,180-240mg qd 維拉帕米 Verapamil HCl 異搏定 40tid/240mgqd,Change in Hemodynamic Profile With Age血壓/心排出量/外周血管阻力的增令性變化,Cardiac Output,Peripheral Resistance,CongestiveHeart Failure,EstablishedHypertension,BorderlineHypertension,Mild,Severe,HemodynamicsBP = CO TPR,Age (years),80,60,40,20,Normal,Messerli FH. J Clin Pharmacol. 1981;21:517-528.,TPRWithCCBOrCarvedilor,CCB & CHD-HT-AR Uptodate 2007,NHTHypertension is a Syndrome !Why focus on hypertension?,CCB & CHD-HT-AR Uptodate 2007,高血壓防治的嚴重性和迫切性,1,Why focus on hypertension?,CCB & CHD-HT-AR Uptodate 2007,USA,中國20041.6億,18.8%18y1.6億,2004,2004全國健康和營養(yǎng)檢測調研,中國高血壓的現(xiàn)狀: 患病率高-18.8%(15y) 知曉率低 44.7, 治療率低 28.2, 達標率低 8.1,降壓達標的重要性: 臨床試驗表明,SP10-14mmHg DP5-6mmHg腦卒中 2/5 40% 冠心病 1/6 16 主要心血管病事件 1/3 33% 2005年中國高血壓防治指南,“ Even a 2 mm Hg lower usual systolic blood pressure would involve about 10% lower stroke mortality and about 7% lower mortality from ischemic heart disease or other vascular causes in middle age.” Lewington S et al. Lancet. 2002;360:1903-1913.,N-RAS & ACEI / ARB,血壓評估和高血壓診斷 中國2005 美國JNC7-2003歐洲2004 心血管事件 (mmHg) (mmHg) (mmHg) 危險性理想血壓Optimal 110/7 115/75 1正常血壓Normal 120/80 120/80 120/80 120-129 / 80-84臨界血壓High-normal 120-139/80-89 120-139/80-89 120-139/80-89 2高血壓 Hypertension 140/或90 140/或 90 140/或 90 140-149 / 90-94 級(輕度) stage 140-159 /或 90-99 140-159 /或 90-99 140-159/或 90-99 4級(中度) stage 160-179/或 100-109 160/或 100 160/或100 級(重度) stage 180 /或110 1180 / 110收縮期高血壓 140 90 140 90 140 90 10降壓達標值 140/90, +DM/KF130/ 80 , +AU1g/d 125/75, 老年SBP 150 mmHg,SBP 比 DBP 對心血管事件的影響更大,Antihypertensive agents:How to choose the right drugs如何選擇藥物,利尿劑:Thiazides: Great efficacy, but may worsen metabolic parameters. -HF, olderACE inhibitors and ARBs: improve insulin resistance and slow progression of renal insufficiency.CCBs: Efficacious, but frequently cause fluid retention.Beta-blockers: Blunt sympathetic tone, but worsen insulin resistance.,A,B,C,D,ACEI/ARB,Beta-B,CCB,Diuretic,Therapeutic Life-staling Change- 治療性生活方式改變飲食，體重，運動，心態(tài)，戒煙.70%,CCB & CHD-HT-AR Uptodate 2007,Antihypertensive response to different drugs in blacks,Materson, BJ et al, N Engl J Med 1993; 328:914. Am J Hypertens 1995; 8:189.,Antihypertensive response to different drugs in whites,發(fā)生任何與藥物相關不良反應的病人百分比,DiUritic,BB,AEEI,CCB,ARB,ARB+HCT,安慰劑,選藥原則:有效性 安全性,可樂定 哌唑嗪,TOMHS Treatment of Mild Hypertension Study輕度高血壓治療的研究,試 驗 目 的確定生活方式改善在輕度高血壓治療中的作用比較五種藥物治療 與生活方式改善對于輕度高血壓治療長期療效與安全性的差異,Neaton JD, et al. JAMA 1993; 270:713 /Uptodate2007,四年的結果: DBP SBP,20,0,1,2,3,4,5,6,7,Cumulative Event Rate (%),0,4,8,12,16,ChlorthalidoneAmlodipineLisinopril,ALLHAT (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n=15,255); amlodipine, 2.5 to 10 mg/d (n=9,048); or lisinopril, 10 to 40 mg/d (n=9,054) for planned follow-up of approximately 4 to 8 years, mean follow-up 4.9 years.ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.,ALLHAT: Cumulative Event Rates for Fatal CHD or Nonfatal MI by Treatment Group高危病人聯(lián)合用藥,Years to Event,Number at Risk:,Chlorthalidone,15,255,14,477,13,820,13,102,11,362,6,340,2,956,209,Amlodipine,9,048,8,576,8,218,7,843,6,824,3,870,1,878,215,Lisinopril,9,054,8,535,8,123,7,711,6,662,3,832,1,770,195,ALLHAT: CCB卒中 vs Diuretic心衰,0.5,1.5,1,0.5,1.5,1,0.5,2,1,Total,Men,Women,Black,Nonblack,Diabetic Patients,Nondiabetic Patients,ALLHAT Collaborative Research Group. JAMA. 2002;288:29812997.,Nonfatal Ml Plus CHD Death,Stroke,HF,FavorsAmlodipine,FavorsChlorthalidone,Favors Amlodipine,FavorsChlorthalidone,Favors Amlodipine,FavorsChlorthalidone,Relative Risk,Relative Risk,Relative Risk,Chlorthalidone (n=15,255)Amlodipine (n=9,048),Cumulative Event Rates for Stroke by ALLHAT Treatment Group,ChlorthalidoneAmlodipineLisinopril,ACEIHCTCCB,ALLHAT ( JAMA 2002; 288:2981-2997),ABCD2,3 (132 mm Hg),AASK1(134 mm Hg),High-Risk Hypertensive Patients Require Multiple Agents to Achieve Goal 高危病人聯(lián)合用藥,1Wright JT et al. JAMA. 2002;288:2421-2431. 2Bakris GL. J Clin Hypertens. 1999;1:141-147. 3Estacio RO et al. N Engl J Med. 1998;338:645-652. 4The ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997. 5Hansson L et al. Lancet. 1998;351:1755-1762. 6Lewis EJ et al. N Engl J Med. 2001;345:851-860. 7Bakris GL et al. Arch Intern Med. 2003;163:1555-1565. 8UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.,Number of BP Medications,ALLHAT4(135 mm Hg),RENAAL7 (140 mm Hg),IDNT6(140 mm Hg),UKPDS2,8 (144 mm Hg),HOT2,5(141 mm Hg),AchievedSystolic BP,Concomitant Use of Antihypertensive Drugs高危病人聯(lián)合用藥- 如何聯(lián)合 ?,Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299-1313.,AASK: Progression of Hypertensive Kidney Disease高血壓腎病 ARB/ACEI BB CCB,230,125,50,0,-35,-55,Baseline,12,6,18,24,30,36,42,48,Amlodipine,Ramipril,Metoprolol,Follow-up (months),Change in Geometric Mean of Proteinuria From Baseline ( %),Percentage Changes in Proteinuria by Randomized Group,Wright JT et al. JAMA. 2002;288:2421-2431.,P.001,n=217,n=436,n=441,AASK=African American Study of Kidney Disease and Hypertension.,ACEI優(yōu)選,Amlodipine,Lisinopril,ALLHAT: Risk of New Diabetes*新發(fā)糖尿CCBDES,5、平滑肌細胞遷移進入內皮下組織,形成新的粥樣斑塊的纖維帽。斑塊增大,6、平滑肌細胞遷移進入內皮下組織和粥樣斑塊的纖維帽。6-7、內皮細胞遷移并且在各種保護因素的作用下形成纖維帽。,8-9、纖維帽在各種促炎癥因素下破裂或損害，表面血小板聚集，形成血栓，導致急生冠脈事件。纖維帽破裂或損傷后，血栓形成，在各種保護因素的作用下，在血栓的表面形成新的纖維帽，使急性冠脈事件，得到新的平衡。,Dynamic Balance of atherosclerosis:Therapeutic implications Eric J.Topol: Textbook of Cardiovascular Medicine 2003; Atherosclerosis P.5-11,The BAsel Stent Kosten Effektivitts Trial - LAte Thrombotic Events (BASKET-LATE),Object to determine the incidence of late clinical events ( 6 months following intervention) related to stent thrombosis in patients treated with DES vs BMS after patients discontinued clopidogrel therapy Study Design patients were randomized in a 2:1 fashion to receive DES or BMS in the BASKET trial. Patients who remained event-free at 6-month follow-up were subsequently enrolled in the BASKET-LATE trial. In the BASKET-LATE trial ,dual antiplatelet therapy was administered for 6 months in all patients regardless of stent type, and clopidogrel was discontinued in all patients after 6 months .Endpoint Patients were followed for an additional 12 months to determine the incidence of cardiac death or nonfatal myocardial infarction (MI) (primary endpoint) and clinically driven restenosis-related target vessel revascularization.,Major cardiac events between 7 and 18 months,Pfisterer ME. American College of Cardiology 2006 Scientific Sessions; March 14, 2006; Atlanta, GA.,100PtsReduse5 RSIncrece3.3pts Thrombosis,Pfisterer ME. American College of Cardiology 2006 Scientific Sessions; March 14, 2006; Atlanta, GA.,USA-TCT Message,Late thrombosis a very-low-frequency event We dont know about the long-term safety of DES in some individualsWe cant predict who is going to have a late clotting riskSome patients never endothelialize the strut of the stent because the drug is so effectiveSome patients have a propensity for thrombosisTell patients that there is a small risk over extended follow-up,Topol,CCB & CHD-HT-AR Uptodate 2007,Stable Angina/ OMI,ESC 2006穩(wěn)定型心絞痛治療指南Fox K, European Heart Journal 2006；27：1341-1381,This guideline updates a previous version: Management of stable angina pectoris. Recommendationsof the Task Force of the European Society of Cardiology. ESC/Eur Heart J 1997 Mar; 18(3):394-413. ACC/AHA 1999; ACC/AHA 2002;,ESC2006穩(wěn)定型心絞痛治療指南Fox K, Alonso Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, DeBacker G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K. Guidelines on the management of stable angina pectoris. Sophia Antipolis, France: European Society of Cardiology; 2006. 63 p. 683 referencesFox K, European Heart Journal 2006；27：1341-1381,2006-ESC- Guidelines on the management of stable angina pectoris,一般治療,急性發(fā)作期吸煙飲食和酒精脂肪酸維生素和抗氧化劑高血壓、糖尿病等運動精神心理駕車性活動就職,2006-ESC-Gui